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Departments of Obstetrics and Gynecology and Pediatrics (J.R.H.) and the Center for Research in Reproduction and Women’s Health, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Christos Coutifaris, M.D., Ph.D., Department of Obstetrics and Gynecology, 106 Dulles Pavilion, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. E-mail: ccoutifaris{at}obgyn.upenn.edu
Osteopontin (OPN), a matrix glycosylated phosphoprotein, has been
proposed to play a role(s) in basic cellular processes, such as
neovascularization and tissue remodeling, which are essential to
placental morphogenesis and embryo implantation. We have shown OPN to
be expressed by cytotrophoblasts of the chorionic villus, and a
putative progesterone regulatory element in the OPN promoter suggests
hormonal regulatory control. This led us to test the hypothesis that
progesterone regulates OPN expression in human cytotrophoblasts.
Cytotrophoblasts isolated from human placentas were treated with
combinations of progesterone, RU486, and/or aminoglutethimide, and
their expression of OPN was assessed by Northern hybridization and
immunocytochemistry. The expression of OPN messenger RNA (mRNA)
declined as trophoblasts aggregated, but rebounded at later times when
syncytia and mononuclear cytotrophoblasts coexisted in culture.
Progesterone increased OPN mRNA expression by aggregating mononuclear
cytotrophoblasts. Aminoglutethimide suppression of endogenous
steroidogenesis by syncytiotrophoblasts inhibited OPN expression,
whereas the addition of exogenous progesterone to cells treated with
aminoglutethimide reversed this inhibitory effect. These observations
were confirmed at the protein level by immunocytochemistry. Treatment
of cytotrophoblasts with both progesterone and RU486 inhibited the
up-regulatory effect on OPN mRNA associated with exposure to
progesterone alone, further confirming a direct effect of progesterone.
We conclude that progesterone up-regulates OPN expression in human
cytotrophoblasts, and we propose that in vivo,
progesterone secretion by syncytiotrophoblasts regulates the expression
of OPN by the underlying cytotrophoblasts. As the receptors for OPN,
v integrins, are expressed by syncytiotrophoblasts, we
postulate that these paracrine regulatory mechanisms contribute to the
adhesive and/or signaling events between the two trophoblast cell types
of the chorionic villus.
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